Multiple myeloma (“MM”) represents a malignant proliferation of plasma cells derived from a single clone. The terms multiple myeloma and myeloma are used interchangeably to refer to the same condition. The myeloma tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms of bone pain or fracture, renal failure, susceptibility to infection, anemia, hypocalcemia, and occasionally clotting abnormalities, neurologic symptoms and vascular manifestations of hyperviscosity. See D. Longo, in Harrison's Principles of Internal Medicine 14th Edition, p. 713 (McGraw-Hill, New York, 1998). Human multiple myeloma remains an incurable hematological malignancy that affects 14,400 new individuals in the United States annually (See Anderson, K. et al., Introduction. Seminars in Oncology 26:1 (1999)). No effective long-term treatment currently exists for MM. It is a malignant disease of plasma cells, manifested as hyperproteinemia, anemia, renal dysfunction, bone lesions, and immunodeficiency. MM is difficult to diagnose early because there may be no symptoms in the early stage. The disease has a progressive course with a median duration of survival of six months when no treatment is given. Systematic chemotherapy is the main treatment, and the current median of survival with chemotherapy is about three years, however fewer than 5% live longer than 10 years (See Anderson, K. et al., Annual Meeting Report 1999. Recent Advances in the Biology and Treatment of Multiple Myeloma (1999)).
While multiple myeloma is considered to be a drug-sensitive disease, almost all patients with MM who initially respond to chemotherapy eventually relapse (See Anderson, K. et al., Annual Meeting Report 1999. Recent Advances in the Biology and Treatment of Multiple Myeloma (1999)). Since the introduction of melphalan and prednisone therapy for MM, numerous multi-drug chemotherapies including Vinca alkaloid, anthracycline, and nitrosourea-based treatment have been tested (See Case, D C et al., (1977) Am. J. Med 63:897–903), but there has still been little improvement in outcome over the past three decades (See Case, D C et al., (1977) Am. J. Med 63:897–903; Otsuki, T. et al, (2000) Cancer Res. 60:1). Thus, the reversal of resistance to chemotherapeutic agents is an important area of research. New methods of treatment such as chemotherapy drugs or combinations are therefore urgently needed for treatment of MM.
The present inventors previously discovered that β-lapachone, when combined with Taxol® (paclitaxel; Bristol-Myers Squibb Co., N.Y., N.Y.) at moderate doses, has effective anti-tumor activity in a human ovarian, prostate and breast cancer xenograft models in nude mice. No signs of toxicity to the mice were observed, and no weight loss was recorded during the subsequent two months following treatment during which the tumors did not reappear (See Li, C J et al. (1999) Proc. Natl. Acad. Sci. USA 96:13369–13374). However, such conditions are different from MM and the current modes of treatment differ as well.
β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho [1,2-b] pyran-5,6-dione), a simple non-water soluble orthonapthoquinone, was first isolated in 1882 by Patemo from the heartwood of the lapacho tree (See Hooker, S C, (1936) I. Am. Chem. Soc. 58:1181–1190; Goncalves de Lima, O, et al., (1962) Rev. Inst. Antibiot. Univ. Recife. 4:3–17). The structure of β-lapachone was established by Hooker in 1896 and it was first synthesized by Fieser in 1927 (Hooker, S C, (1936) I. Am. Chem. Soc. 58:1181–1190). β-lapachone can be obtained by simple sulfuric acid treatment of the naturally occurring lapachol, which is readily isolated from Tabebuia avellenedae growing mainly in Brazil, or is easily synthesized from seeds of lomatia growing in Australia (Li, C J, et al., (1993) J. Biol. Chem. 268:22463–33464).
β-lapachone has been shown to have a variety of pharmacological effects. Numerous derivatives have been synthesized and tested as anti-viral and anti-parasitic agents, and it has been shown to have anti-trypanosomal effects (See Goncalves, A M et al. (1980) Mol. Biochem. Parasitology 1:167–176; Schaffner-Sabba, K. et al. (1984) J. Med. Chem. 27:990–994; Li, C J et al., (1993) Proc. Natl. Acad. Sci. USA 90:1839–1842). β-lapachone significantly prolongs the survival of mice infected with Rauscher leukemia virus, probably through inhibition of reverse transcriptase (Schaffner-Sabba, K. et al. (1984) J. Med. Chem. 27:990–994; Schuerch, A R et al., (1978 Eur. J Biochem. 84:197–205). The present inventors have demonstrated that β-lapachone inhibits viral replication and gene expression directed by the long terminal repeat (LTR) of the human immunodeficiency virus type I (Li, C J et al., (1993) Proc. Natl. Acad. Sci. USA 90:1839–1842).
β-lapachone was investigated as a novel and potent DNA repair inhibitor that sensitizes cells to ionizing radiation and DNA damaging agents (Boorstein, R J et al., (1984) Biochem Biophys. Res. Commun. 118:828–834; Boothman, et al., (1989) Cancer Res. 49:605–612). The present inventors have reported that β-lapachone and its derivatives inhibit eukaryotic topoisomerase I through a different mechanism than does camptothecin, which may be mediated by a direct interaction of β-lapachone with topoisomerase I rather than stabilization of the cleavable complex (Li, C J et al., (1999) J. Biol. Chem. 268:22463–22468). The present inventors and others have reported that β-lapachone induces cell death in human prostate cancer cells (See Li, C J et al., I (1995) Cancer Res. 55:3712–3715). Furthermore, the present inventors found that β-lapachone induces necrosis in human breast cancer cells, and apoptosis in ovary, colon, and pancreatic cancer cells through induction of caspase (Li, YZ et al., (1999) Molecular Medicine 5:232–239).